Examples of the methods described herein are designed to screen for, diagnose, stage severity of, and evaluate response to therapy of liver fibrosis and/or cirrhosis in order to reduce or obviate the need for a liver biopsy in an individual with unsuspected or suspected chronic liver disease.
Liver fibrosis is a condition of liver inflammation and fibrotic scarring that may regress, stabilize or progress to cirrhosis under different treatment conditions. Cirrhosis is a consequence of chronic progressive liver fibrosis and is characterized by replacement of liver tissue by fibrotic scar tissue and regenerative nodules. Cirrhosis may decompensate and lead to liver failure, ascites, varices, hepatocellular carcinoma, hepatic encephalopathy, and death.
Because compensated cirrhosis is asymptomatic, cirrhosis is often undiagnosed, and it is estimated that up to 1% of the U.S. population (3.1 million individuals) may have cirrhosis. Cirrhosis is the eleventh-leading cause of death and responsible for 25,000 deaths in the U.S. each year. Similar numbers have been reported in Europe, and higher numbers are expected in Asia and Africa, where hepatitis C virus (HCV) and hepatitis B virus (HBV) are more common. Most forms of cirrhosis are progressive and lead to the aforementioned complications and death in the absence of a liver transplant, which is an invasive, risky, and expensive.
Cirrhosis is frequently unsuspected and indolent until decompensation, when complications of liver disease are clinically evident. Patients with decompensated cirrhosis present with symptoms of jaundice, ascites, bleeding varices, and/or hepatic encephalopathy, and the diagnosis is made by clinical presentation, medical history, blood laboratory tests, and imaging findings. Occasionally, a liver biopsy is needed to diagnose decompensated cirrhosis. Compensated cirrhosis however is asymptomatic, and diagnosis is typically initiated when an incidental screening test such as liver transaminases or radiologic findings suggest liver disease, and the patients undergo clinical evaluation and liver biopsy.
The most common causes of liver fibrosis and cirrhosis are HCV infection, non-alcoholic fatty liver disease (NAFLD), and alcoholic liver disease, though there are numerous other causes. Currently, the most common cause of liver fibrosis and cirrhosis is HCV infection, which is associated with 15,000 deaths in the U.S. each year. The natural course of HCV infection is variable, though up to 20% of individuals progress to cirrhosis. There is a low risk of progression to severe fibrosis or cirrhosis over 10 to 20 years in patients with HCV and no fibrosis or inflammation. In patients with HCV and bridging fibrosis, there is high risk of progression to cirrhosis.
Up to 30% of the adult U.S. population has NAFLD, which includes simple steatosis, steatosis with inflammation, non-alcoholic steatohepatitis (NASH), and NASH cirrhosis. Because of an association with obesity, which is increasing in incidence, NAFLD and NASH are increasing in incidence. NASH is present in as many as 40% to 75% of patients with NAFLD and elevated transaminases, and many patients with NAFLD and normal transaminases have NASH. NASH has the potential to progress to cirrhosis in 10 to 20% of individuals and is predicted to be the number one cause of cirrhosis in the next decade. Considering the high prevalence of NAFLD in the general population, and that any patient with NAFLD may have NASH, it is estimated that nearly one quarter of the Western population needs screening for NASH (equivalent to 775,000 individuals in the U.S.).
Treatment of liver fibrosis and cirrhosis is aimed at stopping or delaying progression to cirrhosis to reduce or delay complications of decompensated cirrhosis. Not all patients with HCV infection or NAFLD develop liver fibrosis or cirrhosis, and cirrhosis is difficult to diagnose unless it has decompensated and lead to clinically detectable signs of portal hypertension such as ascites or symptomatic varices. By comparison, liver fibrosis and compensated cirrhosis are asymptomatic and cannot be detected without screening measures, even in patients with HCV infection or known NAFLD.
The traditional method for diagnosis of liver fibrosis and cirrhosis of any cause is by random liver biopsy. Staging of liver fibrosis by biopsy in patients with HCV infection is frequently accomplished by the METAVIR system, which categorizes disease into 5 groups (F0 to F4) based on subjective assessment of a histopathology biopsy sample by a hepatopathologist. A similar histological classification method of staging liver fibrosis (F0-F4) is used in NAFLD. Biopsy is a suboptimal clinical tool because of sampling error, subjective qualitative assessment of biopsy samples and classification into categories instead of continuous units, intraobserver and interobserver variation in biopsy result reporting, high cost, relatively long procedure time (especially if conscious sedation is used), low throughput, and risks of pain, bleeding, infection and rarely death. Furthermore, biopsy results are not able to stage the severity of cirrhosis. Staging of cirrhosis is important for prediction and treatment of complications and allocation of liver transplants. Cirrhosis staging is performed via a combination of clinical and laboratory factors as done by Child-Pugh classification or Model for End Stage Liver Disease (MELD) score. The shortcomings of liver biopsy have spurred interest in development of noninvasive tests as a potential alternative to biopsy.
Routine qualitative assessment of medical imaging by ultrasound, computerized tomography (CT), and magnetic resonance imaging (MRI) is generally considered insensitive for detection of cirrhosis and inaccurate for staging the severity of cirrhosis. However, the specificity of subjective medical imaging assessment for extreme liver surface nodularity and varices is high in end-stage cirrhosis. The current role of medical imaging is for the detection of complications of cirrhosis including detection of varices, ascites, hepatocellular carcinoma, and hepatic or portal venous thrombosis. Routine medical imaging is not used in clinical practice to screen for, diagnose, stage severity of, or evaluate response to therapy of liver fibrosis or early stage (compensated) cirrhosis.
Two prominent methods for noninvasively staging liver fibrosis include laboratory tests (predominantly blood tests) and tests that measure the physical stiffness of the liver. A variety of blood tests have moderate to high accuracy (area under the receiver-operating characteristic curve [ROC] median range of 0.59 to 0.86) for differentiating normal and inflamed livers from liver fibrosis and cirrhosis and moderate to high accuracy (ROC median range 0.65 to 0.91) for differentiating noncirrhotic from cirrhotic livers, in individuals HCV infection. Similar accuracies with blood tests have been found in patients with NAFLD.
Increased liver stiffness has been associated with increased liver fibrosis and cirrhosis. A number of techniques have been proposed that provide quantitative physical measures of liver stiffness from imaging or clinical measurement devices. Specifically liver stiffness has been measured by transient elastography (TE), ultrasound shear wave elastography (SWE), ultrasound acoustic radiation force elastography (ARFI), ultrasound strain (static or compression) elastography, magnetic resonance elastography (MRE), and other methods. Each of these methods has moderate to high accuracy for differentiating mild liver fibrosis from severe liver fibrosis and cirrhosis and for differentiating noncirrhotic livers from cirrhotic livers. Problems with transient elastography and ultrasound elastography techniques are limited applicability in moderate to severely obese patients, suboptimal reproducibility of results related to various factors (operator experience, patient body habitus, presence or absence of ascites, etc.), inability to assess the stiffness of the entire liver or central regions of the liver, requirement of a dedicated device to make the measurements, inability to make stiffness measurements on ultrasound images from prior studies without the dedicated device, lack of standardization of methods among different vendors, and false positive cases from other causes of liver stiffness (e.g. liver congestion from cardiac disease). The main problems with MRE are limited applicability in moderate to severely obese patients or in patients with iron overload, requirement of a dedicated device to make the measurements, inability to make stiffness measurements on magnetic resonance images from prior studies without the dedicated device, lack of portability and requirement for a MRI facility, time consuming with low throughput, inability to standardize the technique across multiple scanners and vendors, frequency of individuals with contraindications to MRE (e.g. individuals with pacemakers or severe claustrophobia), high cost, artifacts and failed MRE examinations, and false positive cases from other causes of liver stiffness.
Assessment of segmental liver volume and subjective assessment of liver parenchymal nodularity on medical images for features of severe liver fibrosis and cirrhosis have been evaluated, though overall accuracy of these methods has been poor (<67%), despite the use of imaging experts as readers. The poor accuracy can be attributed to poor inter-observer agreement, particularly in the evaluation for the presence or absence of liver parenchymal nodularity by MRI (overall kappa 0.33 between 3 readers). Similar poor accuracy (45%) has been seen with subjective analysis of liver surface nodularity by high frequency ultrasound. Accuracy for diagnosing cirrhosis by subjective qualitative nodularity assessment on CT images was higher at ROC of 0.92, though interobserver agreement was unsatisfactory for routine clinical practice (kappa 0.75). Even with medical image interpretation by experts, these techniques have not been accepted as having high enough accuracy or reproducibility to be incorporated into clinical practice, particularly since expert readers are not universally available at all points of care for patients with chronic liver disease.
After >25 years of medical imaging of liver disease by CT, MRI and ultrasound, no one has proposed or invented a quantitative method for measuring liver surface nodularity on medical images, until this patent application. Previous methods have all been qualitative, not quantitative, binary assessments for the presence or absence of liver surface nodularity as interpreted by an expert in interpretation of medical images of the liver.
Thus, the present invention meets a long-felt need not accomplished by existing techniques and the prior art.